PTION (provided by applicant): Computational protein design has advanced rapidly from initial studies aimed at increasing the stability of naturally occurring proteins to the recent complete design of a novel protein fold. Our ability to create amino acid sequences compatible with given structures is evidence of the depth of our understanding of the underlying physical determinants of protein stability. Yet, the functions of many proteins depend on the ability of their primary sequences to adopt differing structures in response to changing environmental conditions. To understand this subtle aspect of protein folding, current design algorithms will be improved to optimize the design of a sequence compatible with multiple structures dependent upon environmental context. A select group of proteins will be redesigned to switch structures and this behavior will be experimentally validated. In addition to broadening our understanding of disease causing mutations that interfere with the propensity of cellular proteins for their target structures, these new methods will expand our ability to rationally design molecular switches for medical applications.